Stimulated raman scattering microscopy for evaluation of cancer drug biodistribution Craig Steven 1,2 , Manasa P. Ravindra 1 , Martin Lee 2 , Paul R. J. Davey 3 , Elisabetta Chiarparin 3 , Valerie G. Brunton 2 , and Alison N. Hulme. 1 1 EaStCHEM School of Chemistry, University of Edinburgh, UK, 2 Edinburgh Cancer Research UK Centre, Institute of Genetics & Cancer, University of Edinburgh, UK, 3 Oncology R&D, AstraZeneca, UK. In recent years, stimulated Raman Scattering (SRS) microscopy has emerged as an important tool for drug imaging. By tuning to the vibrational frequency of chemical bonds within a drug’s native structure, label-free imaging can often be achieved, allowing investigation of drug pharmacokinetics, metabolism and biodistribution. 1 Our group has previously shown that this was possible for the tyrosine-kinase inhibitor pontanib, 2 and have now targeted new cancer therapeutics containing Raman-active moieties. However, with ca. 95% of FDA-approved drugs lacking a suitable Raman-active moiety, the development of small, highly Raman-active tags is essential to take full advantage of the technique in drug imaging. Moreover, currently available Raman tags, such as the widely known bisaryl butadiyne (BADY) tag and other polyyne tags, are not optimised for tracking small biomolecules; primarily due to poor solubility and laborious, expensive syntheses. We have considered the physicochemical properties of tag candidates to design and synthesise improved BADY analogues. 3,4 In doing so, we have also shown that small changes in the structure of BADY can effect considerable changes in Raman shift, allowing multiplexity to be achieved. Attachment of these tags to drugs of interest, e.g. the PARP inhibitor olaparib, revealed information on biodistribution for the first time using Raman spectroscopy. 5 Correlation of this information with other biological testing aided in the understanding of the intracellular behaviour of olaparib. State- of-the-art SRS imaging, alongside the development of highly Raman-active tags, has been fruitful in the study of intracellular drug behaviour and will continue to elucidate intricacies of drug action, aiding pre-clinical evaluation of anti-cancer therapies. References 1. C. F. Steven, E. Chiarparin, A. N. Hulme, V. G. Brunton, in Stimulated Raman Scattering Microscopy: Techniques and Applications , Elsevier, 2022, pp. 403–419. 2. K. Sepp, M. Lee, M. T. J. Bluntzer, G. V. Helgason, A. N. Hulme, V. G. Brunton, J. Med. Chem. 2020, 63, 5 , 2028–2034 3. C. F. Steven, M. Lee, G. S. Nichol, P. R. J. Davey, E. Chiarparin, A. N. Hulme, V. G. Brunton, Eur. J. Org. Chem ., 2022, 10 , e202200393. 4. M. P. Ravindra, S. Dimova, C. F. Steven, M. Lee, M. Bluntzer, V. G. Brunton, A. N. Hulme, Manuscript in review . 5. C. F. Steven, M. P. Ravindra, M. Lee, P. R. J. Davey, E. Chiarparin, A. N. Hulme, V. G. Brunton, Proc. SPIE, 2023
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